Mov Disord. 2009 Oct 28;24(S2):S656-S664. [Epub ahead of print]

When does Parkinson's disease begin?
Gaig C, Tolosa E.

Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.

Pathological and neuroimaging studies have shown that in Parkinson's disease (PD) there is a "subclinical" or "premotor" period during which dopaminergic neurons in the substantia nigra (SN) degenerate but typical motor symptoms have not yet developed. Post-mortem studies based on nigral cell counts and evaluating dopamine levels in the striata, and imaging studies assessing the nigrostriatal pathway in vivo, have estimated that this time period could last 3 to 6 years. In addition, emerging evidence indicates that the neuropathological process of PD does not start in the SN but more likely elsewhere in the nervous system: in the lower brainstem and the olfactory bulb, or even more distant from the SN, such as in the peripheral autonomic nervous system. Patients with PD frequently can present non-motor symptoms, such as hyposmia or constipation, years before the development of classical motor signs. The physiopathology of these "premotor" symptoms, though still unclear, is currently thought to be related to early involvement by the pathological process underlying PD of non-dopaminergic lower brainstem structures or autonomic plexuses. However, the answer to the question "when does PD start" remains uncertain. Here, we review clinical, pathological, and neuroimaging data related to the onset of the pathological process of PD, and propose that its onset is non-motor and that non-motor symptoms could begin in many instances 10 and 20 years before onset of motor symptoms. The variable course of the disorder once the motor symptoms develop, suggests that the start and progression of premotor PD is also highly variable andgiven the heterogeneous nature of PD, may differ depending on the cause/s of the syndrome. When and where the neuropathological process develops in PD remains uncertain. (c) 2009 Movement Disorder Society.

PMID: 19877243 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/19877243

OK, so I started to write a book a couple of years ago and realized about half-way through that nobody would read it. Posted it online and never looked back. But this is such a good tie in that I'm going to dust it off and post some of it here. Who knows,it might sway someone with a research budget or something.
From A Matter of Balance:

Preface
When Does the River Become the Sea?

This is but one of a dozen attempts to determine an effective format for the discussion of a quite complicated subject – the origins, causes, processes, course, and cure of Parkinson’s Disease. The complications arise from the fact that there is not “A” cause nor is there “A” cure. An understanding of PD requires the consideration of a Chaotic system, a system governed by the mathematics of a branch of science little known to most neurologists. It is a world in which Lewis Carroll would be at home.

As the result of this complexity it is difficult to convey the picture of PD in a manner both complete and convincing. After trying a range of possible techniques – words, pictures, mind maps, powerpoints, etc – it comes back to words. I have chosen to use this oldest of communication devices to explain some of the newest thoughts.

In particular, I have adopted the format of a barrister addressing a jury of inquest. Such a jury is not about the guilt or innocence of an individual but, rather, it is about finding the facts of a given situation with the expectation of further action by others. And so this is. I wish to lay a case before you for your independent consideration. You are asked to consider the evidence I present and the arguments I make. Identify their weaknesses and their strengths. Investigate the areas that I have overlooked. Discuss the matter amongst yourselves. And decide whether or not the picture I paint of the matter “before the bench” is a logical reflection of reality overall. In particular, you must decide which avenues of investigation are to be followed from this point.

.......

Chapter Two
In the Beginning, There was Stress

Stress. We all know what it is. Don’t we? Or do we just know how it feels? And that just when it is sharp and immediate, i.e. acute. What about the other kind of stress, the chronic. The kind that is not so noticeable because it is always there? The mortgage? The job? The nagging spouse? We even call it the daily grind!

It has been known for a long time that acute stress and chronic stress have vastly different effects. Shock a rat and he tries to escape. Shock a rat that knows there is no escape and he just lies there in despair. Not a pretty image, is it? The two types of stress produce two different chemical cocktails in the body. In acute stress, adrenaline predominates while chronic stress has cortisol in the role. Adrenaline doesn’t last long but gives you the ability to escape the next shock. Cortisol lasts and lasts. And while it helps you bear the next jolt, your system did not evolve with chronic stress and you soon start to break down. Cortisol is a short term asset but a long term liability. Your body is not designed to deal with the constant presence of such a powerful chemical.

The National Institute of Health in 2002 published a report entitled “Stress System Malfunction Could Lead to Serious, Life Threatening Disease” and it is an essential document for understanding this complex subject. <Link>

“A threat to your life or safety triggers a primal physical response from the body, leaving you breathless, heart pounding, and mind racing. From deep within your brain, a chemical signal speeds stress hormones through the bloodstream, priming your body to be alert and ready to escape danger. Concentration becomes more focused, reaction time faster, and strength and agility increase. When the stressful situation ends, hormonal signals switch off the stress response and the body returns to normal.

But in our modern society, stress doesn’t always let up. Many of us now harbor anxiety and worry about daily events and relationships. Stress hormones continue to wash through the system in high levels, never leaving the blood and tissues. And so, the stress response that once gave ancient people the speed and endurance to escape life-threatening dangers runs constantly in many modern people and never shuts down.

Research now shows that such long-term activation of the stress system can have a hazardous, even lethal effect on the body, increasing risk of obesity, heart disease, depression, and a variety of other illnesses.”

Before the advent of the Industrial Age people experienced stress, of course, but it was predominantly acute stress. Once they were attracted to the money offered in the cities the chronic form began to climb. This is a major change over less than a generation. What were the effects, particularly those that might relate to Parkinson’s Disease? We will address that question here only in part, saving the rest for later. At this stage I want to just tell you of the effects in the first year of PD.

You see, the first year of what may become PD is spent mostly in the mother’s womb. We think of this as a protected environment but it has been shown not to always be so. Of particular interest in our inquiry is the role of maternal stress hormones in fetal development. Cortisol and allied chemicals can pass from the maternal bloodstream, bypass the placenta, and enter the fetal environment.

If this occurs during times of critical structure formation, so-called development “windows,” then the effects can be lifelong and more. And more? Yes. It has been shown that stress of a pregnant rat increases the vulnerability to future stress not only of her offspring but that of her “grandchildren” as well!

Reread that last statement. Think of the implications if it is true of humans as well as rats (and there is every reason to think so). This statement leads directly to a conclusion that has earth-shattering properties – namely that in a stressful society that, taken as a whole, stress induced damage will accumulate from one generation to the next. The members of that society will become more and more sensitive to stress and will experience more and more related illnesses. The effects will not manifest in a grand manner but will instead appear gradually in the “weakest links” of the chain of individuals in that society.

In the case of PD and other neurodegenerative conditions, that would mean the old would be the first scattered victims. Then they would become more common. Then the afflicted would gradually become younger and younger. And that is what is slowly happening. How young thus far? Teenagers are not rare.

Members of the jury, we submit to you that Parkinson’s, if it existed at all prior to the mid-1700s, was so rare as to be unknown and that it has risen with modern society to become a scourge that, along with its cousin Alzheimer’s, will devour entire generations if not stopped!

<OK, so I got a little theatrical >

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Chapter Three
From a Single Cell a Life Does Grow

It is, of course, obvious that there are more factors at work than accumulating stress. If that were the only factor the patterns of illness would be more uniform and predictable. And there is indeed much more. For example, consider the lowly bacterium.

There is a huge family of bacteria called gram negative for their response to a particular staining method used to identify them. So huge is this family that most bacteria can claim to be members. They infect our gums and make them bleed. They infect our stomachs and lead to ulcers. They are present in the vagina of ten percent of pregnant women. Sometimes they make their way past the fetal defenses. When this occurs some interesting effects of relevance to this inquiry occur.

For example, a young rat so affected will have fewer dopamine producing neurons in its substantia nigra. It will also have an abnormal (or “dysregulated”) endocrine system that results in unusual stress responses similar to the poor child in Chapter Two. But most importantly here, it will develop, after puberty, an immune system that, particularly in the brain, is “primed” to overly react to further exposure to the bacteria in question.

Actually the reaction is not simply to the presence of the bacteria. Such a simple scenario would be handled by a healthy immune system. No, the problem lies in what must be one of the most diabolical defense tactics in nature. Gram negative bacteria build their cell wall using a molecule called lipopolysaccharide (LPS). LPS is an endotoxin and can, under some circumstances, even be lethal. But so long as it is incorporated in a healthy cell wall it is harmless. However, if your immune system kills that cell a tiny drop of poisonous LPS goes drifting away. And if an antibiotic hits a large colony of such bacteria then a cloud of poison sweeps out into the system. So clever is this defense that some bacteria actually increase the level of LPS dramatically at the first whiff of an antibiotic! A twisted version of the “poison pill” tactics of the business world!

So, a mother’s vaginosis or periodontal disease, for example, interacts with her immune system and a number of dead bacteria release LPS into her bloodstream. A percentage is neutralized by her defenses but a certain amount remains and sometimes a portion of that gets to the fetus and its endocrine and immune systems-to-be.

So the child is born with stress sensitivity, lowered neuronal density, and an immune system set to go off if it ever encounters LPS again, especially in the brain. Here, too, we shall return in our explorations.

............................

Chapter Four
LPS and the Chemistry of Modern Life


Thus we see, the babe is born with an erratic endocrine stress response and an immune system set to over react to further exposure.

The immune system poses a particular danger. Once activated, it inflicts damage to the brain itself! And the triggers are everywhere. In particular, LPS is the primary component of common house dust and we breathe it from Day One. A normal human body can deal with this continuous slow rain of poison by neutralizing and eliminating it without triggering an exaggerated immune response. After all, these are skeletal remnants of long dead foes. It requires cleanup and detox rather than a call to arms.

That is a “normal” response. But what is the response in a sensitized system? The answer is “it depends.” It depends on when, where, who, and how much just for starters. What is the age when it occurs? Pre- or post-puberty, for example? Where is it detected? An infected finger out on the periphery or has the foe breached the blood brain barrier? Is the individual one who has a high, medium, or low sensitivity? And how big is the exposure?

There is a wide range of response to LPS at both the individual and group levels. In a sensitized individual, the immune reaction requires a smaller exposure to elicit a given response. That response includes the release of chemicals called cytokines in greater quantities than the non-sensitized. Among other things, cytokines carry the message to trigger defensive inflammation throughout the system.

And, being a toxin, there is more going on than simply the immune hyper-reaction. If levels are high enough and conditions are right, that reaction is going to be the least of one’s problems.

The reaction varies in detail but a common element is inflammation throughout the system. In the case of a true invader this is appropriate but if there is no enemy other than his long dead remains it quickly becomes self destructive. And when the reaction involves the brain itself that destruction cannot be tolerated and new defenses must be brought into play in order to counter the inflammatory response.

Your body can produce chemicals that counter the excesses of the runaway immune system. Chemicals such as cortisol.

...........................

Chapter Five
Friend or Foe?

A normal endocrine system deals with inflammation by a process that produces cortisol. A normal immune system produces chemicals called cytokines as part of a process that leads to inflammation. Under normal circumstances inflammation is a good thing. It means the invader has been spotted and is under attack. Once he is dealt with, chemical levels return to normal and inflammation subsides. It is part military campaign and part dance. It is very much a balancing act around a normal state of health termed “homeostasis.”

A living system is constantly seeking homeostasis. That is the optimal state for its survival. Neither too hot nor too cold, it is “just right.” The Goldilocks state of being.

In the case before us, the dance has been disrupted. The immune system is out of step due to its hypersensitive reaction to that long ago encounter with LPS. Left to itself, it would never stop the inflammatory response because it would always remain convinced that its old enemy was there somewhere. But this state cannot be safely maintained because of the longterm damage it creates.

A normal response is to release cortisol into the system and trigger the immune system to calm down. But this is anything but a normal situation since both the endocrine-based stress response and the immune-based inflammatory response have both been altered in the womb. So the body does the best it can in hopes of reaching homeostasis. Chronic inflammation? Produce cortisol. Too much cortisol? Produce less. Inflammation starts to increase? Around and around.

The complexity is far greater than a simple see-sawing between two chemicals.

Your body struggles mightily to maintain the dance between immune and endocrine. And it succeeds for awhile. Years. A lifetime even. If you are lucky. But if you are not, then it becomes harder and harder. An infection starts alarm bells. A bad day on the job and sirens wail. The system is making it but just barely at times. Its major system of control of the immune response is cortisol from the endocrine system and it’s on the fritz. Like a pilot at the controls of a fighter plane plunging to earth it struggles to maintain enough cortisol to control inflammation but not so much that its destructive effects upon the hypersensitive system are triggered. As the exploding shells of life’s stressors pepper it with more and more damage, the struggle goes on. Sometimes it is successful and no illness ever develops. Sometimes you get Parkinson's Disease.


...............................

And there I will stop.

Ok, WOW. madelyn

well thought out to say the least.

i and others i know have been known to say that sometimes we think we've had it all our lives. i was a colicky baby. between the bacteria that they now know causes it and the lack of identification of such a thing as "shaken baby syndrome", what are the odds of me not pissing someone off crying 7 hours a day. i imagine i got shaken - everyone has their limits of how much crying they can take. and these are post natal possibilities.

paula